CYTOTOXIC EFFECTS OF TGF-ALPHA-PSEUDOMONAS EXOTOXIN-A FUSION PROTEIN IN HUMAN PANCREATIC-CARCINOMA CELLS

The epidermal growth factor (EGF) receptor is overexpressed in human p ancreatic cancers and cultured cell lines. TP40 is a chimeric protein composed of transforming growth factor-alpha (TGF-alpha) linked to a m odified Pseudomonas exotoxin A (PE40) that exerts growth inhibitory ef fects on cells bearing a high number of EGF receptors. Therefore, we c ompared the effect of TP40 on the growth of Chinese hamster ovary (CHO ) cells expressing varying levels of the EGF receptor and on the growt h of two human pancreatic cancer cell lines. The growth of CHO cells d evoid of endogenous EGF receptors was minimally altered by high concen trations of TP40, even following a 72-h incubation period. In contrast , in CHO cells expressing similar to 95,000 and 438,000 EGF receptors per cell, one-half maximal growth inhibition occurred at 5 and 3 ng/ml TP40, respectively. Following a 72-h incubation in T3M4 and COLO 357 human pancreatic cancer cells, one-half maximal growth inhibition occu rred at 0.2 and 0.4 ng/ml TP40, respectively. This effect was signific antly greater than that of native Pseudomonas exotoxin A. These findin gs indicate that human pancreatic cancer cells are markedly sensitive to the growth inhibitory effects of TP40 and raise the possibility tha t TP40 may have a therapeutic role in this disorder.